The final published report in the New England Journal of Medicine from the VOICE trial of HIV prevention for women in 3 African countries mainly reinforces what conference presentations have already shown: this ambitious trial failed to demonstrate the effectiveness of either oral pre-exposure prophylaxis (PrEP) or of a tenofovir-containing vaginal microbicide gel, and the reason for this was that only 25%-30% of women actually used the study product, despite 88% claiming they did so. The gel, however, may have stopped 2 out of 3 infections among women who used it.

There was one crumb of comfort for the researchers: among women randomized to use tenofovir microbicide gel, there was a 66% reduction in HIV infections among women who actually did use it. However, as the researchers admit, the gel users were not a random sample of trial participants and could have been at less risk of HIV. So the actual efficacy of the gel may have been lower.

The main results of the VOICE trial were reported when they were presented at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta. Briefly, roughly 5000 trial participants from South Africa, Uganda, and Zimbabwe were randomized into 5 groups of just under 1000 each. These 5 groups were allocated to take or use daily:

Retention in the trial was excellent, with 91% of women completing follow-up visits. Adherence appeared to be excellent too, with 86% adherence reported on the basis of women's returns of empty pill boxes and gel applicators.

The end result was that there were actually 49% more HIV infections among participants taking oral tenofovir and 4.4% more among women taking Truvada compared with those taking taking placebo pills, and 14.5% fewer infections among participants using tenofovir gel compared with those using placebo gel. None of these differences were statistically significant.

This was not surprising when drug levels were assessed in a randomly selected 22% of participants who took or used active products (not placebos). Averaged over the course of the study, measurable drug levels were only seen in the blood of 30% of volunteers on tenofovir, 29% of those on Truvada, and 25% of those using the microbicide gel.

Even at the first quarterly visit, only 40% of participants had any drug in their blood and over 50% of participants allocated to use active products never had a single blood test that showed they had actually did so. Not only were these low adherence levels startling, so were the lengths participants had gone to conceal their low adherence. Participants clearly wanted to be in the VOICE trial, but they didn’t want the things it was testing.

Interviews and qualitative studies with the participants after the end of the trial showed a number of different reasons women both had low adherence and concealed it. See this Aidsmap report for a full account, but in general 4 themes emerged:

Participants joined the trial for the pregnancy and HIV testing and the medical monitoring it offered (and possibly for the stipend offered per visit, which was as much as $15).

Participants were afraid of being seen to have HIV drugs and assumed to have HIV.

Participants knew it was a placebo-controlled trial, so they stockpiled their product until there was proof that it worked, or they gave it to others.

Participants believed one of the rumors circulating -- that the drugs were harmful, that they made you infertile, or that they actually gave you HIV.

As the final report says, unfortunately it was those most in need of PrEP who were least likely to adhere to it. Young women under 25 had 40% lower adherence than women over this age, but HIV incidence among younger women taking placebo was nearly 3 times higher than among women over 25.

Similarly, women who had had more than 1 child and married women were respectively only half and one-eighth as likely to acquire HIV as childless and unmarried women, but they were respectively twice and 3 times as likely to take oral PrEP.

Did the Microbicide Gel Have Some Efficacy?

This, however, is where a slight hint of advantage for the microbicide gel starts to creep in. Although the mean 25% adherence to the gel was, according to drug levels in the blood, even lower than in other groups, it was no lower among younger women under 25 than among older women. And although adherence to the gel was higher among married women and those who had more than 1 child, the difference was not as great as it was for oral PrEP.

Furthermore, blood levels of tenofovir may have underestimated adherence to the gel. Vaginal swabs found tenofovir in a mean of 49% of samples. It is possible that the blood levels could tell the true story and, given the elaborate efforts trial participants made to conceal low adherence, the vaginal swab levels could be due to so-called "white-coat dosing" -- using the product solely before clinic visits. Alternatively, if the vaginal levels are reliable, the tenofovir in the gel could simply have failed to penetrate through the tissues and into the bloodstream in sufficient amounts to be detected.

Either way, women allocated to the microbicide gel with detectable blood levels of tenofovir were the only group in the whole study who benefited from significant protection against HIV. HIV incidence among members of the tenofovir gel arm with no drug detected was 9.1% a year, while among those with drug detected it was 1.9% year. After this was adjusted for the fact that women with detectable drug levels were more likely to be married and have had children, and therefore less at risk of HIV, there remained nonetheless a significant 66% reduction in HIV infections among women with evidence in their blood that they had used the gel (hazard ratio 0.34; p=0.02).

In contrast, having detectable tenofovir in the blood was not protective for oral PrEP users. This at first seems a greater puzzle. However, the threshold for drug detection was set at very low levels, so detectable drug may not have indicated adherence sufficient to protect against infection.

The 66% reduction in HIV infections among gel users is not a randomized result. As the researchers say, although they can adjust for the type of person gel users were, they cannot adjust for actual HIV exposure. It is possible that better adherence to the gel was correlated with lower vulnerability to HIV for a reason the researchers did not control for -- lower levels of domestic violence or forced sex, for instance.

However, the finding that the tenofovir gel, if used, may have offered some protection is one positive result in a trial that was in other ways a shock and, as a recent New York Times report emphasized, a challenge to researchers to remodel how they do prevention studies with disadvantaged groups. It may also bode well for the results of the FACTS 001 tenofovir-gel microbicide trial in South Africa, which will report its results at this year’s CROI conference in 2 weeks.